Phosphatase and tensin homolog deleted on chromosome ten (PTEN [MIM 601728]) is a ubiquitous tumor suppressor that plays a role in both heritable and sporadic neoplasias (Zbuk, K. M., et al. Nat. Rev. Cancer, 7:35-45 (2007)). Cowden syndrome (CS [MIM 158350]) is a difficult to recognize, autosomal dominant inherited cancer syndrome characterized by benign and malignant breast, thyroid and endometrial neoplasias in addition to cutaneous findings and macrocephaly (Eng, C., Hum. Mut., 22:183-198 (2003)). Germline PTEN mutations have been found in 85% of those with classic CS while 15% remain mutation negative despite extensive analyses including the promoter and looking for large deletions and rearrangements (Marsh, D. J., et al., Hum. Mol. Genet., 7:507-515 (1998); Zhou, X. P., et al., Am. J. Hum. Genet., 73:404-411 (2003)). Many more patients with features reminiscent of CS, not meeting diagnostic criteria (National Comprehensive Cancer Center Practice Guidelines (NCC); Table 1) and referred to as CS-like, are evaluated by clinicians for CS and cancer-risk. CS is believed to be without genetic heterogeneity (Nelen, M. R., et al., Nat. Genet., 13:114-116 (1996)) to date, only PTEN has been implicated in this syndrome. However, there likely exist other susceptibility genes for CS and CS-like phenotypes, especially in the latter, which appear to be a heterogeneous disease.
Therefore, a better understanding of CS syndrome and CS-like syndrome is needed in order to provide better detection methods for these syndromes.